대한요로생식기감염학회지제 1 호제 1 권 2006 년 10 월 Korean J UTII Vol.1, No.1, October 2006 종설 세균성요로감염치료의현재와미래 2) 가톨릭대학교의과대학비뇨기과학교실 조용현 [Abstract] Present and Future Strategies in the Treatment of Bacterial Urinary Tract Infection Yong-Hyun Cho From the Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea Bacterial urinary tract infections (UTIs) are common infectious diseases that can be associated with substantial morbidity and significant expenditures. The mainstay of management of UTIs is almost exclusively antibiotic agent. There are two predominant aims in the antibacterial treatment of UTIs: (i) rapid and effective response to therapy and prevention of recurrence of the individual patient treated; (ii) prevention of emergence of resistance to antimicrobial chemotherapy in the microbial environment. The main drawback of current antibiotic therapies is the emergence and rapid increase of antibiotic resistance. To combat this, active research is going on. This review highlights the current concepts and recent advances in our understandings and future treatment options for UTIs. (Korean J UTII 2006;1:17-23) 서 요로감염은흔히발생될수있으며또한항생제투여로비교적용이하게치유될수있는, 질환으로취급되는것이일반적인생각이다. 그러나여성의경우 40-50% 는일생에최소한한번은요로감염을경험하며그중상당수는반복적으로감염된다. 1 대부분의감염은급성으로진행되고단기간내에치유되지만경우에따라서는치료에저항할수도있고신기능의손실및심한경우생명의위험을초래하기도한다. 이러한경우환자들의신체적피해뿐만아니라이로인하여소요되는경제적및사회적비용은엄청나다. 요로감염은신장, 신우, 요관, 방광및요도로이어지는 론 교신저자 : 조용현가톨릭대학교의과대학비뇨기과학교실서울영등포구여의도동 62 Tel:02-3779-1024, Fax:02-761-1626 E-mail: cyh0831@catholic.ac.kr 요로를구성하는모든부위와그주변기관인신주위근막, 전립선, 그리고부고환등에도요로를통한균의침범으로발생할수있다. 현재이러한요로감염치료의가장중요한근간은항생제치료라는것은이견의여지가없을것이다. 감염질환의치료를위한항생제치료는효과적이어야하며재발방지그리고항생제내성균주출현을억제할수있는방향으로이루어져야한다. 그러나현재이러한기준에모두부합하는요로감염치료에이상적인항생제는존재하지않는다. 또한현재우리는항생제내성이라는또하나의극복해야할장벽을만나게되었으며, 이는기존의항생제치료의효과를위협하고있는실정이다. 따라서이상적인항생제의개발을위해현재다양한연구및치료가시도되고있다. 이에저자는현재그리고새로이개발되는항생제의특성및향후시도될수있는요로감염의치료방법에대해서정리하고자한다. 17
18 대한요로생식기감염학회지 : 제 1 호제 1 권 2006 년 10 월 본론 1. 세균성요로감염치료및예방의현재현재의요로감염에대한약물적치료및예방에있어서가장주된것은항생제이고다른하나는백신이다. 1) 항생제일반적으로항생제의효과는시험관내살균력과혈중농도수치를측정하여평가한다. 그러나요로감염치료를위한항생제의효과는신실질, 방광, 전립선등실제조직에서의항생제의농도가매우중요하다. 그럼에도불구하고체내조직에서의항생제농도를측정하기란쉬운일은아니기때문에대신요중항생제농도및살균력을측정하여요로감염치료에적절한지를평가한다. 2 현재퀴놀론제제는단순요로감염 (uncomplicated UTI) 뿐만아니라복잡성요로감염 (complicated UTI) 에서도광범위한항균력을가지고있어가장먼저선택되어지는항생제이다. 이러한퀴놀론은종류별로매우다양한배설능의차이를보이고있으며높은배설능을보이는항생제가요로감염에효과적이라고알려져있다. 낮은배설능 (40% 이하 ) 을보이는퀴놀론제제로는 norfloxaxin (20%), gemifloxacin (28%), moxifloxacin (20%), pefloxacin (14%) 등이며중간정도의배설능 (40-75%) 을보이는퀴놀론제제로는 ciprofloxacin (43%), enoxacin (53%), fleroxacin (67%) 등이며 gatifloxacin (80%), levofloxacin (84%), lomefloxacin (75%) 그리고 ofloxacin (81%) 등은높은배설능 (75% 이상 ) 을보이는퀴놀론제제로보고되고있다. 2 현재까지중간이상의배설능을보이는퀴놀론제제의대부분이요로감염치료에적절한것으로인정이되어사용되고있다. 반면최근에개발된 gemifloxacin과 moxifloxacin 은 3상임상시험상 ciprofloxaxin, levofloxacin등과비교하여우월한효과를입증하지못하고매우실망스런결과가나오고있는실정 (data on Bayer Healthcare, SmithKline Beecham) 이므로현재까지는요로감염치료에적응이되지못하고있는실정이다. 지금까지살펴본바에의하면요로감염치료를위한항생제선택에있어서항균력, 혈중농도등을포함해요중배설능을고려하는것이매우 중요함을알수있다. 현재의항생제치료에있어서가장큰문제점은내성균주의발현및증가일것이다. 3 우선퀴놀론의작용기전을살펴보면세포내에 DNA gyrase 또는 topoisomerase IV의두개의표적에작용하는데, DNA gyrase 에부착하여 DNA-gyrase-quinolone 복합체를형성하고이복합체가 DNA 복제복합체 (DNA replication complex) 에장벽으로작용하여 DNA 복제를방해한다. Topoisomerase IV 는복제된 DNA가서로연결되어있을때이들의분리를촉매하는효소로 DNA-topoisomerase IV-quinolone 복합체를형성하여 DNA복제를방해한다. 일반적으로그람음성균에서는 DNA gyrase 가퀴놀론의일차표적으로작용하고그람양성균에서는 topoisomerase IV가일차적인표적이된다. 그람음성균의퀴놀론내성기전은 gyrase를코딩하는유전자인 gyra 또는 gyrb의변이에의하여발생하는경우가가장흔하며그람양성균에대한내성기전은 topoisomerase IV를코딩하는 parc 유전자의변이에의하여발생하는경우가흔하다. 3 현재까지는주로이러한항생제내성균주발현및증가에발맞추어다른작용기전을갖고있는새로운항생제개발에주력을해왔다. 그러나분명새로운항생제개발에는한계가있을수있으며향후에는새로운관점의치료법이가능성을보이고있다. 여기에대에서는다시언급하겠다. 2) 백신현재요로감염의예방을위해면역력증강을목적으로투여할수있는약제는유로박솜 과스트로박 이다. 두약제다반복적인단순요로감염환자를대상으로투여하는요로감염균주에서추출한항원을이용하여제조한균체용해물이다. 유로박솜 은경구용제제로 Escherichia coli (E. coli) 중실제로요로감염을일으키는균주에서추출한항원을이용, 복용시 E. coli에대한특이적항체가분비돼면역인자가활성화된다. 4 Bauer 등은반복적요로감염을앓는여성환자들을대상으로유로박솜 에대한위약군을대조군으로하여이중맹검법으로진행된 5개의임상시험, 총 601명을대상으로메타분석한결과에서유로박솜 투여군에서뚜렷한요로감염횟수의감소가확인되어요로감염예방에효과가있다고보고하
조용현 : 세균성요로감염의치료의현재와미래 19 였다. 4 최근 453명의반복적요로감염을앓는여성들을대상으로한다기관임상시험에서유로박솜 치료군이대조군에비해요로감염을 43% 감소시켰다고보고하였다. 6 이보고에서특히주목해야할점은 1년간의추적관찰을시행장기간의예방효과를확인할수있었다는것이다. 유로박솜 의요로감염에대한예방효과는지금까지의보고로확인할수있다. 그러면현재널리추천되는재발성요로감염에대한예방용법들과비교하면어떻게될까? Albert 등 7 은재발성요로감염에대한저용량항생제예방요법은대조군에비해 81% 의요로감염횟수를감소시킨다고보고하였으나현재까지유로박솜 과항생제투여를직접적으로비교한임상시험은진행되지않아서위에물음에대한답은시간이필요할것이다. 반면스트로박 은 E.coli뿐만아니라 Pseudomonas mirabilis, Klebsiella pneumonia, Morganella morganii, Escherichia faecalis 등의균주에서추출한복합균주추출물이다. 8 이론적으로는 E.coli외에도다른여러요로감염균에대한면역획득을기대할수있으나경구제제 가아닌주사제제이기때문에한계가있는실정이다. 2. 세균성요로감염치료의미래현재세균성요로감염치료를위협하는가장중요한요소로는내성균주의출현및증가일것이다. 이러한항생제내성균주에의한치료의저항을극복하기위해서다양한연구가진행되어왔다. 현재까지가장활발하고실제임상에근접한방법은새로운항생제개발이다. 이와더불어항생제의침투력을증대시켜효율성을높이는방법과항생제대체물질에관한연구가진행되어왔다. 1) 새로운항생제의개발및시도항생제투여에따른내성균주의출현은현실적으로감염질환의치료에있어서중요한문제에봉착하게된다. 이러한내성균주출현에따라새로운화학요법제제가개발, 시도되어지고있다. 이러한화학요법제제는기존의항생제에생체이용률의향상, 반감기의연장, 침투력등을조절하여치료효율을높이는방법, 기존의타장기나다 Table 1. Emerging chemotherapeutic agents Antibiotic substance class Bacterial spectrum & characteristics Urinary excretion G(+) pathogens including MRSA and VRE, not active against G(-) 78% The high urinary excretion promises activity in UTI. Daptomycin8-12 Lipopetide-antibiotic The large molecule might hinder distribution into urinary tract tissues. The specific Gram-positive activity restricts the substance to treatment of a relative small proportion of UTIs Good activity against G(+) including MRSA and VRE, and E. coli, Klebsiella Tigecycline13 Glycylcyline Enterobacter spp. 14% The relatively low urinary excretion might be a potential drawback in the treatment of UTI Anti-MRSA cephalosporin 90% Against G(-) comparable activity to group 3 and 4 cephalosporins Ceftobiprole14 Cephalosporin Because of the wide range of activity against most uropathogens and the high urinary excretion, the substance is of potential interest in the treatment of UTI Ciprofloxacin Exerts identical antibacterial activity as ciprofloxacin 40% XR15-17 Fluoroquinolone (extended release) Ciprofloxacin XR is a once daily formulation, overall comparable to twice daily ciprofloxacin Good antibacterial activity against G(+), but in comparison to other Balofloxacin18 Fluoroquinolone fluoroquinolones decreased activity against G(-). 86% Balofloxacin is in the treatment of UTI probably not superior to other fluoroquinolones Garenoxocin19 Des-F(6)-quinolone Good antibacterial activity against G(+). Activity against G(-) is comparable to fluoroquinolones, such as ciprofloxacin or levofloxacin. It seems that garenoxacin 30-40% exerts also activity against fluoroquinolone resistant strains.
20 대한요로생식기감염학회지 : 제 1 호제 1 권 2006 년 10 월 른질환에사용하였던항생제의요로감염으로의적용하는방법그리고항균스펙트럼, 생체이용률, 살균력등을향상시킨새로운항생제를개발하는방법등이있다. 요로감염에적절한항생제로인정받기위해서는어떠한조건들이필요할까? 여러조건들이필요하겠지만그중에서도요로감염균주를포함하는항균스펙트럼, 요중산도변화에따른지속적인항균력유지그리고무엇보다도중요한것은충분한요중배설능력일것이다. 저자들은최근새로이시도되어지고있는항생제들의항균스펙트럼, 요중배설능력그리고임상적특징을정리하였다 (Table 1). 9-20 2) 항생제의세포내침투를증대시키기위한노력항생제세포투과도의변화또는세포내항균물질의세포외배출은다양한항생제내성획득기전중매우잘알려진기전이다. 이러한 efflux-pump는세포막에존재하는폴리펩티드로이 pump의작용으로세포내유입된항생제를세포외로유출시키게되어내성을획득하게된다. 21 이러한 efflux-pump의억제가항생제의치료효과를올리며내성발현을억제할수있을것이라는이론적배경에서시험관내실험및제한적으로생체실험을시행 Efflux-pump 억제제를항생제와병용투여시항균력의상승작용을확인할수있었으며더나아가항생제내성균주출현을감소시킬수있다고하였다. 21,22 Efflux-pump 억제제와같이항생제의세포내농도를높여서항생제의치료효과를향상시키기위한또다른시도로철의대사과정을이용하였다. 철의유입과배출은매우중요한세균대사이며이철대사과정에서 Siderophore는세포외철의세포내유입과정에서중개역할 (mediator) 을하면서직접세포내로유입된다. 이에착안하여 Siderophore와항생제를결합시켜항생제의세포내유입의증가로항균력의증가를보여치료효율성향상의가능성을제기하였으며, 23 실제로베타락탐을 siderophore와결합시켜 Pseudomonas aeruginosa, Escherichia coli, Klebsiella pneumoniae, Serratia marcescens 등의그람음성세균들을대상으로한시험관내 (In vitro) 실험에서증가된항균력을보고하였다. 24 향후동물실험을거쳐활발한임상시험이기대되고있다. 3) 항생제의대체물질의개발및시도최근연구되고있는요로감염의치료방법중하나는기존의항생제의작용기전들과는전혀다른 Bacteriophage나 Bacteriophage enzyme을이용한항생제의대체제에관한것이다. 장기간항생제를투여하여야하는경우내성균주의출현뿐만아니라정상균총의변화에따른부작용도상당수발생할수있다. Bacteriophage는세균에침투, 감염을일으키는일종의바이러스이다. 이러한 Bacteriophage는세균을숙주로세균의복제과정중동시에자기복제및증식을수행하는데, 복제후자기의후손 (progeny) 들을퍼뜨리기위해서는세균의세포벽을뚫고나가야하는문제가발생한다. 이러한문제를해결하기위해서 Bacteriophage 스스로가세포벽을녹일수있는효소들을분비하게되어세균의세포벽은용해되게된다. 이러한개념을이용실제감염을일으키는균주를표적으로하는 Bacteriophage를생성, 주입하여정상균총에는영향을미치지않고항균효과를가질수있다는것이다. 25 이러한시도는동물실험모델에서집락형성된균총을대상으로진행되었고, 질점막내세균을대상으로시행한동물실험에서효과를볼수있었다고보고하였다. 26,27 Bacteriophage를이용한세균감염치료의시도는앞으로더많은연구가필요하겠지만기존항생제의단점을보완할수있어서항생제치료를대체할수있을지관심을끌고있다. 결론최근들어내성균주발현의증가는요로감염치료에있어서가장중요한근간인항생제의치료효과를위협하기시작했다. 이러한위협에대해새로운항생제의개발이시도되고 Efflux-pump 억제제나 Siderophore 같은항생제의침투력을높이는방법, Bacteriophage등을이용한항생제를대체할수있는제제에관한연구가진행되고있으나아직까지는보다심도깊고전문적인연구가필요한상황이다. 요로감염치료를위한가장중요한근간이항생제라
조용현 : 세균성요로감염의치료의현재와미래 21 는것은누구나인정할것이다. 그러나단순히항생제투여가치료의전부라고생각하기에는부족함이있다. 효과적인요로감염치료를위해서는항균력뿐만아니라요중배설능등항생제의특성에대한전반적이해가반드시선행되어야하며, 이러한이해없는항생제의사용은효율적인치료를위협하고내성균주의출현을가속화시키게될것이다. REFERENCES 1. Foxman B. Epidermilology of urinary tract infections: incidence, morbidity, and economic costs, Am J Med 2002;113(S1A):5S-13S 2. Naber KG. Which fluoroquinolones are suitable for the treatment of urinary tract infections? Int J Antimicrob Agents 2001;17:331-41 3. Naber KG, Wagenlehner F. Antibiotics and resistance of uropathogens. EAU Update Series 2004;2:125-35 4. Bauer H, Blebmann GS, Pitrow DB, Rahlfs VW. Prevention of recurrent urinary tract infections with immunoactive E. coli fractions. Eur J Obstet Gyn 1999;86:33 5. Bauer HW, Rahlfs VW, Lauener PA, Blessmann GS. Prevention of recurrent urinary tract infections with immuno-active E. coli fractions: a meta-analysis of five placebo-controlled double-blind studies. Int J Antimicrob Agents 2002;19:451-6 6. Bauer HW, Alloussi S, Egger G, Blumlein HM, Cozma G, Schulman CC; Multicenter UTI Study Group. A long-term, multicenter, double-blind study of an Escherichia coli extract (OM-89) in female patients with recurrent urinary tract infections. Eur Urol 2005;47:542-8 7. Albert X, Huertas I, Pereiro II, Sanfelix J, Gosalbes V, Perrota C. Antibiotics for preventing recurrent urinary tract infection in non-pregnant women Cochrane Database Syst Rev. 2004;3:CD001209 8. Riedasch G, Möhring K. Immunisierungstherapie rezidivierender Harnwegsinfekte der Frau. Therapiewoche 1986;6:896-900 9. Snydman DR, Jacobus NV, McDermott LA, Lonks JR, Boyce JM. Comparative In vitro activities of daptomycin and vancomycin against resistant gram-positive pathogens. Antimicrob Agents Chemother 2000;44:3447-50 10. Laganas V, Alder J, Silverman JA. In vitro bactericidal activities of daptomycin against Staphylococcus aureus and Enterococcus faecalis are not mediated by inhibition of lipoteichoic acid biosynthesis. Antimicrob Agents Chemother 2003;47:2682-4 11. Fuchs PC, Barry AL, Brown SD. In vitro bactericidal activity of daptomycin against staphylococci. J Antimicrob Chemother 2002;49:467-70 12. Louie A, Kaw P, Liu W, Jumbe N, Miller MH, Drusano GL. Pharmacodynamics of daptomycin in a murine thigh model of Staphylococcus aureus infection. Antimicrob Agents Chemother 2001;45:845-51 13. Woodworth JR, Nyhart EH Jr, Brier GL, Wolny JD, Black HR. Single-dose pharmacokinetics and antibacterial activity of daptomycin, a new lipopeptide antibiotic, in healthy volunteers. Antimicrob Agents Chemother 1992;36:318-25 14. Rubinstein E, Vaughan D. Tigecycline: a novel glycylcycline. Drugs 2005;65:1317-36 15. Heinzl S. Neue Antibiotika. Chemotherapie Journal 2005;14:54-57 16. Henry DC Jr, Bettis RB, Riffer E, Haverstock DC, Kowalsky SF, Manning K, et al. Comparison of once-daily extendedrelease ciprofloxacin and conventional twice-daily ciprofloxacin for the treatment of uncomplicated urinary tract infection in women. Clin Ther 2002;24:2088-104 17. Wagenlehner FM, Kinzig-Schippers M, Tischmeyer U, Wagenlehner C, Sorgel F, Dalhoff A et al. Pharmacokinetics of ciprofloxacin XR (1000 mg) versus levofloxacin (500 mg) in plasma and urine of male and female healthy volunteers receiving a single oral dose. Int J Antimicrob Agents 2006;27:7-14 18. Talan DA, Naber KG, Palou J, Elkharrat D. Extendedrelease ciprofloxacin (Cipro XR) for treatment of urinary tract infections. Int J Antimicrob Agents 2004;23(Sl):54-66 19. Rubinstein E. History of quinolones and their side effects, Chemotherapy 2001;47(S3):3 8 20. Dalhoff A, Schmitz FJ. In vitro antibacterial activity and pharmacodynamics of new quinolones. Eur J Clin Microbiol Infect Dis 2003;22:203-21 21. Kaatz GW. Bacterial efflux pump inhibition. Curr Opin Investig Drugs 2005;6:191-8 22. Kaatz GW. Inhibition of bacterial efflux pumps: a new strategy to combat increasing antimicrobial agent resistance. Expert Opin Emerg Drugs 2002;7:223-233 23. Heinisch L, Wittmann S, Stoiber T, Scherlitz-Hofmann I, Ankel-Fuchs D et al. Synthesis and biological activity of tris-
22 대한요로생식기감염학회지 : 제 1 호제 1 권 2006 년 10 월 and tetrakiscatecholate siderophores based on poly-aza alkanoic acids or alkylbenzoic acids and their conjugates with beta-lactam antibiotics. Arzneimittelforschung 2003;53:188-95 24. Wittmann S, Schnabelrauch M, Scherlitz-Hofmann I, Mollmann U, Ankel-Fuchs D, Heinisch L. New synthetic siderophores and their beta-lactam conjugates based on diamino acids and dipeptides. Bioorg Med Chem 2002;10:1659-70. 25. Fischetti VA. Bacteriophage lytic enzymes: novel antiinfectives. Trends Microbiol 2005;13:491 6 26. Cheng Q, Nelson D, Zhu S, Fischetti VA. Removal of group B streptococci colonizing the vagina and oropharynx of mice with a bacteriophage lytic enzyme. Antimicrob Agents Chemother 2005;49:111 7 27. Yoong P, Schuch R, Nelson D, Fischetti VA. Identification of a broadly active phage lytic enzyme with lethal activity against antibiotic-resistant Enterococcus faecalis and Enterococcus faecium. J Bacteriol 2004;186:4808-12